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Treatment


18 to 36 months.29,30


Therefore, for patients with remission duration ≥ 18 months, consolidation with second stem cell transplantation is a valid option. In this regard, there does not appear to be a clear signal that the type of high-dose therapy given with the salvage ASCT has a significant impact on outcome, and in the absence of prospective trial data, many centres continue to use single agent high-dose melphalan, although other strategies such as the combination of bortezomib and melphalan in this setting has been evaluated.31,32


Reduced-intensity conditioning AlloSCT in the salvage setting is sometimes considered for younger patients with good performance status and high-risk features, including del 17p, t(4;14), t(14;16), or high-risk gene expression profile, high lactate dehydrogenase, or plasma cell leukaemia. Prospective randomised studies comparing salvage AlloSCT with salvage ASCT have not been performed but several retrospective analyses have shown improved PFS for patients undergoing salvage AlloSCT but have not shown an OS benefit.33


Other regimens and new agents in development


Several regimens such as cyclophosphamide–bortezomib– dexamethasone (CyBord), bortezomib– lenalidomide–dexamethasone (VRD) or pomalidomide–bortezomib– dexamethasone (PVd)4


IMiDs


Thalidomide Lenalidomide Pomalidomide


G2 S RAS


Proteasome inhibitors Bortezomib Carfilzomib Ixazomib Marizomib


RAF


MAPK MEK


P13K Akt


mTORC2 mTORC2


Alkylators Melphalan


Cyclophosphamide Bendamustine Melflulen


Kinase inhibitors CKD 1,2,5,9 Dinaciclib FGF3 Dovitinib


VEGF-R Bevacizumab


Signalling pathways


mTORC1 Everolimus/Temsirolimus mTORC2 MLN0128/INK128 P38/JNK act Aplidin


M


G0/G1 arrest


MoAb G1


CS-1 Elotuzumab CD38 Daratumumab/ SAR650984 IL-6 Siltuximab CD138 nBT062-DM4


DACI


Panobinostat Vorinostat Romidepsin


Adapted from: Ocio E et al. New drugs and novel mechanisms of action in multiple myeloma in 2013: a report from IMWG. Leukemia 2014; 28:525-542.


Figure 2: Schematic representation of the main targets in plasma cells in multiple myeloma. Approved drugs are shown in red and drugs that have reached Phase III are shown in green.


was reported when combined with lenalidomide and dexamethasone.37,38 Finally, the anti-CD38 antibodies daratumumab and SAR650984 have shown impressive single-agent activity in heavily pretreated patients and are being explored in combination with other agents even for patients with newly diagnosed MM.39,40


Special populations have been tested for


patients who are double-refractory to an IMiD and to bortezomib. However, patients with relapsed and refractory disease who have been exposed to thalidomide, lenalidomide and bortezomib still have limited treatment choices and a very poor prognosis, highlighting an unmet clinical need and an urgent requirement for the development of safe and effective therapies for this patient population.34


As noted in


Figure 2, over 30 novel agents are in different phases of development many of which have already been clinically tested.35 Among them, particular attention should be paid to the histone deacetylase inhibitor panobinostat and the monoclonal antibodies elotuzumab (anti-SLAMF7), daratumumab, and SAR650984 (anti- CD38). The addition of panobinostat to bortezomib and dexamethasone significantly improved PFS (11.99 vs 8.08 months, p<0.0001) in patients with RRMM.36


Although single-agent


elotuzumab lacks activity in RRMM patients, an objective response rate of 82%


Renal failure is a severe complication associated with shorter survival especially in the relapse setting. Bortezomib-based regimens are highly active in these patients without needing any dose adjustment. Recent data also support the use of carfilzomib as a feasible option for these patients because of its clearance independent of renal function. By contrast, the increased risk of thromboembolic events in patients with MM associated with the use of IMiD-based therapies and bortezomib-based regimens should also be considered as the most appropriate approach for these patients. The presence of polyneuropathy is the most commonly treatment-limiting complication with thalidomide and bortezomib therapies. While the use of the subcutaneous formulation of bortezomib could be a valid option for these patients, lenalidomide- based strategies are also a useful alternative in this setting.41


In the presence of severe bone lesions or plasmacytomas, bortezomib has an anabolic effect on the bone as a result of


inhibition of human osteoclast differentiation, and its use with radiotherapy should be considered.42 Finally, several groups have reported encouraging results with bortezomib-based regimens in patients with high-risk cytogenetics. Likewise, recently available data also suggest the use of carfilzomib- and pomalidomide-based combinations for the treatment of this high-risk subgroup of patients.22,43


Conclusions


Although most myeloma patients achieve disease control with current therapies, almost all will subsequently relapse or progress, necessitating additional treatment. In this scenario, it is mandatory to try to follow a systematic approach. Patients with RRMM require carefully consideration of individual relapse characteristics. Among them, the type (early versus late) and number of relapses and the efficacy and toxicity observed with the previously administered regimens are especially relevant factors. Several other considerations such as performance status, age, comorbidities, renal impairment, and bone marrow reserve need also to be considered when deciding which is the best alternative for a given patient.44 Currently there are a large number of regimens for patients with RRMM but more options will become available in the near future. These new agents are creating opportunities to target multiple pathways, overcome resistance, and improve clinical


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